The delivery of a drug to a patient with controlled-release of the active ingredient has been an active area of research for decades and has been fueled by the many recent developments in polymer science and the need to deliver more labile pharmaceutical agents such as nucleic acids, proteins, and peptides. In addition, controlled release polymer systems can be designed to provide a drug level in the optimum range over a longer period of time than other drug delivery methods, thus increasing the efficacy of the drug and minimizing problems with patient compliance.
Biodegradable particles have been developed as sustained release vehicles used in the administration of small molecule drugs as well as protein and peptide drugs and nucleic acids (Langer, Science, 249:1527-1533, 1990; Mulligan, Science, 260:926-932, 1993; Eldridge, Mol. Immunol., 28:287-294, 1991, the entire teaching of each of the foregoing references are incorporated herein by reference). The drugs are typically encapsulated in a polymer matrix which is biodegradable and biocompatible. As the polymer is degraded and/or as the drug diffuses out of the polymer, the drug is released into the body. Typically, polymers used in preparing these particles are polyesters such as poly(glycolide-co-lactide) (PLGA), polyglycolic acid, poly-β-hydroxybutyrate, and polyacrylic acid ester. These particles have the additional advantage of protecting the drug from degradation by the body. Furthermore, these particles depending on their size, composition, and the drug being delivered can be administered to an individual using any route available.
Targeting controlled release polymer systems (e.g., targeted to a particular tissue or cell type or targeted to a specific diseased tissue but not normal tissue) is desirable because it reduces the amount of a drug present in tissues of the body that are not targeted. This is particularly important when treating a condition such as cancer where it is desirable that a cytotoxic dose of the drug is delivered to cancer cells without killing the surrounding non-cancerous tissue. Effective drug targeting should reduce the undesirable and sometimes life threatening side effects common in anticancer therapy.
With advances in immunology and molecular biology, it is now possible to target specific tissues or cells directly by using antibodies or antibody fragments to antigens unique to or more prevalent in the target tissue or cell. Antibodies have been used for immunotherapy directly or as vehicles to deliver drugs to tissues or cells. However, this approach was first attempted using monoclonal antibodies to deliver chemotherapeutic agents in the 1980's and proved to be considerably more difficult than anticipated. Several obstacles including immunotoxicity, poor tumor/plasma distribution and poor tumor penetration by the antibodies. Immunotoxicity has been mitigated by using humanized and engineered monoclonal antibodies. However, poor tumor/plasma distribution and poor tumor penetration by the antibodies has been attributed to the large size of monoclonal antibodies and remains an important consideration today. Despite recent success of monoclonal antibodies as drugs, this class of molecule continues to exhibit suboptimal properties as vehicles for drug delivery, largely because of their large size.
Moreover, the biological production of monoclonal antibodies can be difficult and unpredictable. Antibody generation can be difficult if the target antigen is not well tolerated by the animal used to produce the antibodies (e.g., toxins). Furthermore, some target molecules are inherently less immunogenic making it difficult to raise antibodies against such targets. In addition, the performance of antibodies can vary from batch to batch, in particular when production is scaled-up.
It would be desirable to develop drug targeting vehicles that that can be used to target the delivery of controlled release polymer systems like monoclonal antibodies with high specificity but which overcome or ameliorate some of the problems associated with the use and production of monoclonal antibodies.